We propose to investigate a neural mechanism underlying propensity to consume alcohol. This mechanism was initially studied as being important in stress-induced depression, and now appears to prominently regulate the propensity to consume alcohol as well. We will focus on the relationship between activity of locus coeruleus (LC) neurons, the major noradrenergic cell body group in the brain, and dopamine neurons in the ventral tegmentum (VTA-DA neurons) that represent the cell bodies of the mesocorticolimbic dopaminergic system. Specifically, we will study, and, most importantly, will herein present evidence indicating that willingness (or propensity) to consume alcohol derives from ethanol profoundly inhibiting the burst firing of LC neurons, which, by so doing, reduces an inhibitory influence on VTA-DA neurons, thereby enabling ethanol to markedly increase firing of VTA-DA neurons that will support (promote) alcohol consumption. For these studies, we will use a rat line that we initially developed, through selective breeding, for its stress susceptibility (called Susceptible or SUS rats). Subsequently, we found that rats of this line show a pronounced propensity to consume alcohol, unlike any of our other lines of selectively-bred lines or normal Sprague-Dawley (SD) rats which will not voluntarily consume alcohol. SUS rats in fact drink as much alcohol as rat lines that have been specifically developed for their propensity to consume alcohol, and the amount of alcohol that SUS rats voluntarily consume clearly has pharmacological effects. Additionally, and perhaps related to stress-susceptibility of SUS rats, these animals show a phenomenon that researchers have attempted for many years to demonstrate in rodents, and even in alcohol-preferring rodents - namely, SUS rats increase their alcohol consumption when exposed to stress, and thereby show stress-induced increases in alcohol consumption. We will study how the neural relationship described above is affected by stress, and how effects on this relationship may explain stress-induced increases in alcohol consumption. In Aim 1, we test the proposed mechanism by selectively increasing or decreasing LC activity in SUS rats and then measuring (a) intake of alcohol and (b) conditioned place preference (CPP) induced by ethanol injections. Ethanol intake and CPP should decrease when LC activity is increased, and vice versa. In Aim 2, we will record the response of VTA-DA neurons to alcohol while experimentally increasing or decreasing LC activity as in Aim 1. Lastly, Aim 3 will determine if stress-induced increases in alcohol intake of SUS rats are accompanied by (a) greater inhibition of LC burst firing, and (b) larger VTA-DA excitation by alcohol. PUBLIC HEALTH RELEVANCE: Having developed in our laboratory a line of rats that shows a marked sensitivity to stress (called the Swim-test Susceptible, or SUS rat), we subsequently observed that SUS rats, in contrast to normal rats, show a decided propensity to consume alcohol and, important here, an increase in alcohol consumption after exposure to stressful conditions. We propose, and plan to test, a potential neurobiological mechanism that may underlie both the innate and stress-induced enhancement of the propensity to consume large amounts of alcohol by SUS rats, possibly relevant to other lines of alcohol-preferring rodents and human alcoholics as well.